Infection by Hepatitis C virus (HCV) is a compelling human medical problem. HCV is recognized as the causative agent for most cases of non-A, non-B hepatitis, with an estimated human sero-prevalence of 3% globally. Nearly four million individuals may be infected in the United States alone.
Of persons who become infected with HCV, 20-25% may be able to clear the virus after the acute infection, but 75-80% will develop chronic Hepatitis C infection. This usually results in recurrent and progressively worsening liver inflammation, which often leads to more severe disease states such as cirrhosis and hepatocellular carcinoma. Unfortunately, there are no broadly effective treatments for the debilitating progression of chronic HCV.
The HCV genome encodes a polyprotein of 3010-3033 amino acids. The HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication. The NS proteins are derived by proteolytic cleavage of the polyprotein.
The HCV NS protein 3 (NS3) contains a serine protease activity that helps process the majority of the viral enzymes, and is thus considered essential for viral replication and infectivity. It is known that mutations in the yellow fever virus NS3 protease decreases viral infectivity. The first 181 amino acids of NS3 (residues 1027-1207 of the viral polyprotein) have been shown to contain the serine protease domain of NS3 that processes all four downstream sites of the HCV polyprotein.
The HCV NS3 serine protease and its associated cofactor, NS4A, helps process all of the viral enzymes, and is thus considered essential for viral replication. This processing appears to be analogous to that carried out by the human immunodeficiency virus aspartyl protease, which is also involved in viral enzyme processing. HIV protease inhibitors, which inhibit viral protein processing are potent antiviral agents in man, indicating that interrupting this stage of the viral life cycle results in therapeutically active agents. Consequently it is an attractive target for drug discovery.
There are not currently any satisfactory anti-HCV agents or treatments. Until recently, the only established therapy for HCV disease was interferon treatment. The first approved therapy for HCV infection was treatment with standard (non-pegylated) interferon alfa. However, interferons have significant side effects and interferon alfa monotherapy induces long term remission in only a fraction (˜25%) of cases. The addition of ribavirin to the treatment regimen increases response rates slightly. Recent introductions of the pegylated forms of interferon (PEG-INTRON® and PEGASYS®), which has also been combined with ribavirin have resulted in only modest improvements in remission rates and only partial reductions in side effects. (PEG refers to polyethyleneglycol.) The current standard of care is a treatment regimen lasting 24-48 weeks, depending on prognostic factors such as HCV genotype and demonstration of initial response to therapy. The majority of HCV genotype-1 patients do not achieve sustained virologic response (SVR) after a 48-week regimen of pegylated interferon-alfa-2a/2b and ribavirin. Moreover, retreatment of prior PR non-responders (null and partial responders) and relapsers with pegylated interferon and ribavirin achieves SVR rates of less than 10% and 30%, respectively. The prospects for effective anti-HCV vaccines remain uncertain.
Thus, there is a need for anti-HCV therapies and appropriate dose regimens for anti-HCV compounds.
HCV and other diseases and disorders are associated with liver damage. There is also a need for therapies and appropriate dose regimens for treating liver damage.
Dosing regimens for VX-950 are described in PCT Publication Numbers WO 2006/050250 and WO 2008/144072, which are incorporated herein by reference in their entirety. Additional dosing regimens for VX-950 are described in PCT Serial Number PCT/US2008/012460, filed on Nov. 4, 2008, which is incorporated herein by reference in its entirety.